Micafungin is a novel anti-fungal drug of pneumocandins, and it inhibits the synthesis of a fungi cell wall component, i.e. β-1,3-D-glucan synthase, whereby destroying the structure of fungal cells and thus leading to cytolysis. Micafungin is widely used for treating various infections, such as infections caused by Aspergillus, Candida, Cryptococcus, Mucor, Actinomyces, Histoplasma, Dermatophytes and Fusarium and the like.
Micafungin Sodium (also named as FK463) is the active pharmaceutical ingredient of the marketed drug, Mycamine. The chemical structure of micafungin Sodium is shown as follows:

Sodium 5-[(1S,2S)-2-[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)-3-[(R)-2-carbamoyl-1-hydroxyethyl]-11,20,21,25-tetrahydroxy-15-[(R)-1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-18-[4-[5-(4-pentoxyphenyl)isoxazol-3-yl]benzoylamino]-1,4,7,13,16,22-hexaazatricyclo[22.3.0.09,13]heptacosan-6-yl]-1,2-dihydroxyethyl]-2-hydroxy phenyl sulfate.
The compound of formula I is a polypeptide compound with poor stability, and its quality and efficacy are affected by degradation products generated during transportation or long-term storage. Furthermore, the compound of formula I is difficult to be crystallized and generally it is in an amorphous state.
U.S. Pat. Nos. 6,107,458 and 7,199,248 and WO 96/111210 disclosed methods for preparing and purifying the compounds of Formula I. Wherein, in U.S. Pat. No. 7,199,248, Micafungin DIPEA (diisopropylethylamine) salt was purified through filtration and chromatographic separation, and then precipitated with acetone and ethyl acetate to give the amorphous form of the compound of formula I.
Atsushi Ohigashi et at, “Process Development of Micafungin, a Novel Lipopeptide Antifungal Agent”, Journal of Synthesis Organic Chemistry, 2006, Vol 64 (12), described that the compound of formula I can be precipitated by adding a mixture of acetone and ethyl acetate to the elution solution of the compound of formula I from ion exchange, so as to give the amorphous compound of formula I. Before drying, the content of solvent in the precipitate of the compound of formula I was high (Dry/Wet=0.25), and the precipitate of the compound of formula I contained about 75% of solvent. To effectively remove the solvent, the drying time has to be extended, which, however, will cause an increase in the degradation products of the compound of formula I and a reduction in purity.
All the compounds of formula I obtained by the above prior art methods are in amorphous form. Compared with molecules in a crystalline solid material, molecules in an amorphous solid material possess higher energy, because the orderly and periodic arrangement of molecules will reduce the energy of the interaction between molecules. In accordance with the principles of thermodynamics, high-energy materials have poor stability, while low-energy materials have good stability. In general, the stability of a compound in amorphous state is less than that of the crystal thereof.
In addition, the patent application WO 03/018615 a Fujisawa Pharmaceutical Co., Ltd. disclosed a new crystal form of the compound of the formula I and a preparation method thereof. In WO03/018615, the compound of formula I in amorphous form was dissolved in an aqueous solution of a single alcohol or an aqueous solution of acetone, and a solvent, such as ethyl acetate, methylene chloride, acetone and acetonitrile, was added, so as to give the B82-type acicular crystals of the compound of formula I. The crystal was obtained in an organic solvent, has a needle shape under microscope, and has peaks at the following 2θ angles in the X-ray powder diffraction pattern: 4.6°, 5.5°, 9.0°, 9.8°, 16.9°.
In “Study of Industrial Manufacturing Methods for Micafungin (FK463)”, Seibutsa kogaku Kaishi, 2005, Vol 83, YAMASHITA, et al., from Fujisawa Pharmaceutical Co., Ltd., mentioned that needle-like crystals of FK463 were successfully obtained through optimization of solvent and control of pH. However, no specific embodiments and crystal data were disclosed. Since the prior patent application WO03/018615 of the company disclosed the B82-type needle-like crystals of the compounds of formula I, it can be seen that what YAMASHITA et al. obtained was also the B82-type needle-like crystal.
The present inventors prepared the B82-type acicular crystal according to the method of Example 1 in WO03/018615, and the resultant crystal was observed with an optical microscope, which reveals that the crystal is about 1 μm in size and has a fine-needle shape. When the crystals were subjected to subsequent processing steps, such as filtration, drying or the like, the present inventors found that, because the B82-type crystals essentially have a fine-needle morphology, it is difficult to filter the crystals of the compound of formula I and the operation needs a long time; before drying of the crystals, the content of solvent in the compound of formula I (Dry/Wet) was about 0.25, and a large amount of organic solvent was trapped in the crystal. To render the content of solvent in compliance with the requirements for active pharmaceutical ingredients (API), the drying temperature or the drying time has to be increased during the drying process. Such drying process, however, will increase the degradation product of the compound of formula I, seriously affecting the quality and stability of API.
At present, the disclosed Micafungin sodium solids are of poor stability and can only be stored at a low temperature or lyophilized with the presence of a large amount of excipients to ensure its stability, which greatly limits the development of pharmaceutical uses of Micafungin sodium. If a stable solid of Micafungin sodium can be found, it can be prepared into various formulations, such as lyophilized powder for injection, tablets, capsules, ointment, etc., to facilitate the use by different patients.
Therefore, there is an urgent need in the art to obtain a new crystalline form of the compound of formula I which is more stable, and easier to be filtered and dried, so that a better commercial production can be achieved.